Numerous systems participate in the integrated processes that cause an animal to seek and ingest food, and to stop eating when more food is available. This project relates to the acute effects of ingesting large numbers of calories at 1 time, for whereas supplying new nutrients to the body is the ultimate goal of eating, it can only be accomplished by perturbing the delicate balance of circulating nutrients, at least on a temporary basis. Because of this, animals have evolved elaborate strategies to minimize the acute impact of meals on blood glucose and other nutrients. Many of these adaptive responses are made in anticipation of eating large meals, and they and their consequences are the focus of this proposal. We have also found that meal-fed animals that consume all of their daily food in a short period of time have greatly improved glucose tolerance at the time they are expecting food. The goal of this project is to understand the mechanisms underlying this adaptation in order to inform future therapies. Based upon our novel observations, we have developed 3 specific aims. Specific Aim 1 will utilize euglycemic hyperinsulinemic or hyperglycemic clamps to identify the metabolic adaptations responsible for improved glucose tolerance, testing specific hypotheses concerning changes in peripheral insulin resistance, glucose disposal rate and/or B-cell function. These experiments will utilize laboratory rats and mice. Specific Aim 2 will test the hypothesis that a comparable battery of food anticipatory responses occurs when ad lib-fed rats anticipate eating large meals. Specific Aim 3 will test the hypothesis that meal-fed rats are enabled to eat large amounts of food in a short period of time because they have become relatively unresponsive to satiety signals. This project will identify behavioral approaches that improve glucose tolerance. Because impaired glucose tolerance is a major symptom of diabetes mellitus and many instances of obesity, and because most current therapies achieve only modest improvements in glucose tolerance, the proposed research has considerable and compelling health implications; i.e., based on the proposed research, novel therapies for individuals with impaired glucose tolerance might include specific eating regimens that would yield powerful health benefits to complement pharmacological approaches. [unreadable] [unreadable]